Theoretical Evaluation of Alternamides A and B from Alternanthera Littoralis As Potential Antioxidant Agents

Alternamides A and B, two catechol-containing alkaloids isolated from Alternanthera littoralis P. Beauv., have been experimentally associated with the radical scavenging potency of the plant extract, but their detailed radical-scavenging mechanisms remain unclear. In this study, density functional theory calculations were performed to evaluate the antioxidant potential of alternamide A (AA) and alternamide B (AB) in aqueous and lipid-like environments. Thermodynamic descriptors, including bond dissociation enthalpy, ionization potential, and proton affinity, were analyzed to clarify the preferred formal hydrogen atom transfer, single electron transfer, and sequential proton loss electron transfer pathways. Kinetic calculations were further conducted for the reaction with the HOO• radical under physiological conditions. The thermodynamic results indicate that the hydroxyl groups are the preferred reactive sites, whereas the N–H positions are less favorable for radical scavenging. AB generally shows lower BDE, IP, and PA values than AA, suggesting stronger intrinsic antioxidant potential, particularly at the 7-OH position. At physiological pH, both compounds exist mainly in neutral forms, but their minor monoanionic populations dominate the aqueous radical-scavenging activity through the SET pathway. The overall rate constants of AA and AB in water are 1.43 × 10⁸ and 2.18 × 10⁸ M− 1 s− 1, respectively. After accounting for the molar fractions of both the antioxidant species and HOO•, the fully corrected overall rate constants are (3.59 × 105 and 5.47 × 105 M− 1 s− 1) for AA and AB, respectively, which are markedly higher than that of Trolox. In contrast, in the lipid-like medium, ionized species are less stabilized and the fHAT mechanism becomes dominant, giving lower overall rate constants of 3.14 × 10⁴ and 1.55 × 10⁴ M− 1 s− 1 for AA and AB, respectively. These findings demonstrate that alternamides A and B are efficient antioxidants in aqueous physiological environments, with AB showing superior activity, while their lipid-phase activity is moderate and mainly governed by hydrogen atom transfer.